Social control of lifespan regulation via glial plasticity in ants

摘要 与神经退行性疾病相关的神经退行性疾病构成了巨大的生物医学挑战。大脑的可塑性变化 支持与衰老相关的认知能力下降和神经退行性变，但对神经保护作用知之甚少。 在健康老化的大脑中阻止这些过程的途径。在哺乳动物中， 性能显示与年龄相关的动态，包括向更神经保护功能的转变， 年龄在果蝇中，神经胶质也与调节大脑健康和寿命有关，强调了一个深刻的 神经胶质功能的进化保守性。 这项提案的目标是确定胶质细胞如何促进健康的大脑衰老和长寿， Harpegnathos saltator ants，一个强大的模式系统，研究分子和表观遗传调控， 衰老成年Harpegnathos工人可以通过表型转变成为女王（称为“gamergates”） 可以延长五倍的寿命 我们在工人过渡到长寿的gamergates之前和之后进行了单细胞RNA测序， 发现了神经胶质的显著可塑性。具体来说，我们发现成鞘胶质细胞基本上 在gamergate的大脑中扩展。有趣的是，当它们被激活时， 然而，工人的大脑在他们的一生中迅速耗尽了这些细胞。 成鞘胶质细胞对损伤作出反应，并提供一般的管家和神经保护功能， 但它们并不知道有助于健康的大脑老化和长寿。我们的数据表明， 假设扩大的成鞘胶质细胞室有助于延长寿命， 游戏门 在目标1中，我们将确定伴随成鞘胶质细胞的分子和细胞变化 在工人和游戏者的不同老化过程中的动力学。在目标2中，我们将研究特定的 一种在成鞘神经胶质细胞中表达的受体，可能直接调节它们对 一种生殖基因在游戏鼠中的表达在目标3中，我们将利用原代蚂蚁神经元培养物， 在果蝇中进行基因操作，以确定成鞘胶质细胞和寿命之间的因果关系， 其机制。 总之，我们的工作将阐明1）控制神经胶质可塑性的新分子途径，2）新的生物学作用 神经胶质可塑性，以及3）神经胶质细胞调节健康大脑衰老的机制。

ABSTRACT Age-related neurodegenerative diseases pose an immense biomedical challenge. Plastic changes in the brain underpin aging-related cognitive decline and neurodegeneration but little is known about the neuroprotective pathways that forestall these processes in healthy aging brains. In mammals, glia composition and properties display age-related dynamics including a shift to a more neuroprotective function as the brain ages. In Drosophila, glia are also implicated in regulating brain health and lifespan, underscoring a deep evolutionary conservation of glia function. The goal of this proposal is to determine how glia contribute to healthy brain aging and longevity using Harpegnathos saltator ants, a powerful model system to study the molecular and epigenetic regulation of aging. Adult Harpegnathos workers can become queens (called “gamergates”) via a phenotypic transition that results in a 5-fold extension of lifespan. We performed single-cell RNA-seq before and after the transition of workers to long-lived gamergates and found remarkable plasticity in the glia. Specifically, we found that ensheathing glia cells were substantially expanded in gamergate brains. Interestingly, gamergates retained high levels of ensheathing glia as they aged, whereas worker brains were rapidly depleted of these cells over the course of their life. Ensheathing glia cells respond to damage and provide general housekeeping and neuroprotective functions in Drosophila but they are not known to contribute to healthy brain aging and longevity. Our data suggest the hypothesis that an expanded ensheathing glia compartment contributes to the prolonged lifespan of gamergates. In Aim 1, we will determine the molecular and cellular changes that accompany the ensheathing glia dynamics during differential aging in worker and gamergates. In Aim 2, we will investigate the role of a specific receptor that is expressed in ensheathing glia cells and might directly regulate their expansion in response to the expression of a reproductive gene in gamergates. In Aim 3, we will utilize primary ant neuronal cultures and genetic manipulations in Drosophila to determine the causal link between ensheathing glia and longevity and its mechanism. Together, our work will elucidate 1) new molecular pathways that control glia plasticity, 2) a new biological role for glia plasticity, and 3) mechanisms for the regulation of healthy brain aging by glia.